scholarly journals The Vildagliptin Experience – 25 Years Since the Initiation of the Novartis Glucagon-like Peptide-1 Based Therapy Programme and 10 Years Since the First Vildagliptin Registration

2017 ◽  
Vol 13 (02) ◽  
pp. 56 ◽  
Author(s):  
James E Foley ◽  
Bo Ahrén ◽  
◽  
Keyword(s):  
Glycaemic Control ◽  
Mechanism Of Action ◽  
Incretin Hormone ◽  
Dipeptidyl Peptidase 4 ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Improved Glycaemic Control ◽  
Kinetics Of ◽  
Therapy Programme

The discovery of the incretin hormone glucagon like peptide-1 (GLP-1), and its usefulness in the treatment of type 2 diabetes mellitus (T2DM) followed by the finding that dipeptidyl peptidase-4 (DPP-4) inhibition prevents GLP-1 inactivation, led to the discovery of DPP-728. In 1999, studies with DPP-728 established the first proof-of-concept that DPP-4 inhibition improves glycaemic control in patients with T2DM. Further efforts to improve the binding kinetics of DPP-728 resulted in the discovery of vildagliptin (LAF237). In the last 20 years, a plethora of studies conducted by Novartis in collaboration with external investigators has demonstrated the mechanism of action of vildagliptin and its efficacy as monotherapy and as an add-on therapy for patients with T2DM. The studies establish that vildagliptin is a selective DPP-4 inhibitor that blocks GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) inactivation, thereby prolonging their action, resulting in improved glycaemic control. This review aims to discuss the discovery and development of vildagliptin, with an emphasis on mechanism of action and clinical efficacy.

scholarly journals A sandwich ELISA for measurement of the primary glucagon-like peptide-1 metabolite

2017 ◽  
Vol 313 (3) ◽  
pp. E284-E291 ◽  
Author(s):  
Nicolai J. Wewer Albrechtsen ◽  
Ali Asmar ◽  
Frederik Jensen ◽  
Signe Törang ◽  
Lene Simonsen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Sandwich Elisa ◽  
Active Form ◽  
Primary Metabolite ◽  
Incretin Hormone ◽  
Dipeptidyl Peptidase 4 ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted from the gastrointestinal tract. It is best known for its glucose-dependent insulinotropic effects. GLP-1 is secreted in its intact (active) form (7–36NH2) but is rapidly degraded by the dipeptidyl peptidase 4 (DPP-4) enzyme, converting >90% to the primary metabolite (9–36NH2) before reaching the targets via the circulation. Although originally thought to be inactive or antagonistic, GLP-1 9–36NH2 may have independent actions, and it is therefore relevant to be able to measure it. Because reliable assays were not available, we developed a sandwich ELISA recognizing both GLP-1 9–36NH2 and nonamidated GLP-1 9–37. The ELISA was validated using analytical assay validation guidelines and by comparing it to a subtraction-based method, hitherto employed for estimation of GLP-1 9–36NH2. Its accuracy was evaluated from measurements of plasma obtained during intravenous infusions (1.5 pmol × kg−1 × min−1) of GLP-1 7–36NH2 in healthy subjects and patients with type 2 diabetes. Plasma levels of the endogenous GLP-1 metabolite increased during a meal challenge in patients with type 2 diabetes, and treatment with a DPP-4 inhibitor fully blocked its formation. Accurate measurements of the GLP-1 metabolite may contribute to understanding its physiology and role of GLP-1 in diabetes.

Subcutaneous glucagon-like peptide-1 improves postprandial glycaemic control over a 3-week period in patients with early Type 2 diabetes

1998 ◽  
Vol 95 (3) ◽  
pp. 325-329 ◽  
Author(s):  
Jeannie F. TODD ◽  
C. Mark B. EDWARDS ◽  
Mohammad A. GHATEI ◽  
Hugh M. MATHER ◽  
Stephen R. BLOOM
Keyword(s):  
Type 2 Diabetes ◽  
Glycaemic Control ◽  
Plasma Glucose ◽  
Test Meal ◽  
Insulin Response ◽  
Standard Test ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
First Phase Insulin Response

1.Glucagon-like peptide-1 (7-36) amide (GLP-1) is released into the circulation after meals and is the most potent physiological insulinotropic hormone in man. GLP-1 has the advantages over other therapeutic agents for Type 2 diabetes of also suppressing glucagon secretion and delaying gastric emptying. One of the initial abnormalities of Type 2 diabetes is the loss of the first-phase insulin response, leading to postprandial hyperglycaemia. 2.To investigate the therapeutic potential of GLP-1 in Type 2 diabetes, six patients were entered into a 6-week, double-blind crossover trial during which each received 3 weeks treatment with subcutaneous GLP-1 or saline, self-administered three times a day immediately before meals. A standard test meal was given at the beginning and end of each treatment period. 3.GLP-1 reduced plasma glucose area under the curve (AUC) after the standard test meal by 58% (AUC, 0–240 ;min: GLP-1 start of treatment, 196±141 ;mmol·min-1·l-1; saline start of treatment, 469±124 ;mmol·min-1·l-1; F = 16.4, P< 0.05). The plasma insulin excursions were significantly higher with GLP-1 compared with saline over the initial postprandial 30 ;min, the time period during which the GLP-1 concentration was considerably elevated. The plasma glucagon levels were significantly lower over the 240-min postprandial period with GLP-1 treatment. The beneficial effects of GLP-1 on plasma glucose, insulin and glucagon concentrations were fully maintained for the 3-week treatment period. 4.We have demonstrated a significant improvement in postprandial glycaemic control with subcutaneous GLP-1 treatment. GLP-1 improves glycaemic control partially by restoring the first-phase insulin response and suppressing glucagon and is a potential treatment for Type 2 diabetes.

scholarly journals Glucagon-Like Peptide 1: A Predictor of Type 2 Diabetes?

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Matthias Ploug Larsen ◽  
Signe Sørensen Torekov
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Acids ◽  
Fasting Glucose ◽  
Incretin Effect ◽  
Nonesterified Fatty Acids ◽  
Incretin Hormone ◽  
Pubmed Database ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Background. The incretin effect is impaired in patients with type 2 diabetes. Aim. To assess the relation between the incretin hormone GLP-1 and the prediabetic subtypes: impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and the combined IFG/IGT to investigate whether a low GLP-1 response may be a predictor of prediabetes in adults. Method. 298 articles were found using a broad search phrase on the PubMed database and after the assessment of titles and abstracts 19 articles were included. Results and Discussion. Studies assessing i-IFG/IFG and i-IGT/IGT found both increased, unaltered, and reduced GLP-1 levels. Studies assessing IFG/IGT found unaltered or reduced GLP-1 levels. When assessing the five studies with the largest sample size, it clearly suggests a decreased GLP-1 response in IFG/IGT subjects. Several other factors (BMI, glucagon, age, and nonesterified fatty acids (NEFA)), including medications (metformin), may also influence the secretion of GLP-1. Conclusion. This review suggests that the GLP-1 response is a variable in prediabetes possibly due to a varying GLP-1-secreting profile during the development and progression of type 2 diabetes or difference in the measurement technique. Longitudinal prospective studies are needed to assess whether a reduced GLP-1 response is a predictor of diabetes.

scholarly journals Effects of GLP-1 and Incretin-Based Therapies on Gastrointestinal Motor Function

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Chinmay S. Marathe ◽  
Christopher K. Rayner ◽  
Karen L. Jones ◽  
Michael Horowitz
Keyword(s):  
Inhibitory Action ◽  
Current Knowledge ◽  
Incretin Hormone ◽  
Distal Small Intestine ◽  
Gastrointestinal Motor ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Antiobesity Agents ◽  
Motor Actions

Glucagon-like peptide 1 (GLP-1) is a hormone secreted predominantly by the distal small intestine and colon and released in response to enteral nutrient exposure. GLP-1-based therapies are now used widely in the management of type 2 diabetes and have the potential to be effective antiobesity agents. Although widely known as an incretin hormone, there is a growing body of evidence that GLP-1 also acts as an enterogastrone, with profound effects on the gastrointestinal motor system. Moreover, the effects of GLP-1 on gastrointestinal motility appear to be pivotal to its effect of reducing postprandial glycaemic excursions and may, potentially, represent the dominant mechanism. This review summarizes current knowledge of the enterogastrone properties of GLP-1, focusing on its effects on gut motility at physiological and pharmacological concentrations, and the motor actions of incretin-based therapies. While of potential importance, the inhibitory action of GLP-1 on gastric acid secretion is beyond the scope of this paper.

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